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Wednesday, May 21, 2014

At the annual gathering of the gene therapy community today, Tekmira presented an update on
their ongoing phase I trial with TKM-Ebola, the company’s biodefense
candidate for the treatment of Ebola infection developed with funding by the US government (press release here, presentation here). I have long considered this to be a 'thankless' trial, a real ‘Haertetest’ of SNALP delivery because a) Tekmira took the risk
of not employing transient immune suppression as it otherwise does, and b) the multi-ascending dose
schedule (5x daily) would be as intense as in no other setting. While taking on all these safety risks, the
company would not be able to balance any safety findings with efficacy/knockdown data in this safety trial.

Indeed, what we got today was an update from the
single-ascending dose part of the study which showed a dose-limiting toxicity (DLT) in the form of immune stimulation resulting in the potentially serious condition of
hypotension at the top, 0.5mg/kg dose level.

From the many emails I have received and message board postings
that I have read on InvestorVillage, it seems that a common misinterpretation of the data was that they reflected poorly on the safety of 3rd gen SNALP delivery, the most recent and
most potent version of SNALP.

It is important to emphasize that the reason why we saw this DLT in this study, but not in the various,
preceding SNALP-enabled studies such as TKM-PLK1 (1st gen),
ALN-TTR01 (1st gen), ALN-TTR02 (2nd gen), or
ALN-PCS02 (2nd gen), is because Tekmira did not employ the transient
immune suppression around the time of dosing that has become routine for SNALP
technology following a similar finding of immune stimulation in the first-ever
trial with SNALP-RNAi, TKM-ApoB (2009/2010).

What it means for the pipeline

This means that if the company re-adopted transient immune
suppression for their other pipeline candidates, there would not be all that
much to worry about with regard to encountering this type of immune stimulation again. Transient immune suppression will not
matter much for most of the diseases of high unmet need and severity pursued by
Tekmira and partners (e.g. cancer, TTR amyloidosis).

The reason why Tekmira likely did not employ transient
immune suppression for TKM-Ebola is because the help by the immune
system is thought to be an important adjunct mechanism to achieving cures with an RNAi
approach to this highly severe, acute infection. Moreover, suppressing the immune
system might actually make the Ebola infection worse than it already is.

For other viral infections, especially HBV, the issues become more
complex. For example, it is known that
with immune suppression such as steroids or certain monoclonal antibody
therapies, HBV may dangerously reactivate.
However, if the immune suppression was only transient (~1 day versus an
RNAi duration of activity of weeks), I am not aware that the same risks exist. Moreover, doing something to get
the virus out of its hiding place and then coming in to knock it down may actually result in the highest cure rates just as the likelihood of e-antigen seroconversion
increases in immune active versus immune silent patients.

Another part of the equation would be whether doses anywhere
near 0.5mg/kg would be required for 3rd generation SNALP-based TKM-HBV. If say 0.15mg/kg or less would be enough,
transient immune suppression may not need to be considered.

What it means for TKM-EBOLA

Today’s data raises most uncertainty with regard to
TKM-EBOLA and the timeline of potential stockpiling. In the non-human primate studies, it was the
0.5mg/kg dose that resulted in 100% protection in a post-exposure treatment
setting. If the 0.5mg/kg dose level
would have been clean in the current trial, I would have been very optimistic
about the prospect of accelerated stockpiling, even before full FDA
approval. At 0.2mg/kg in the NHP
studies, protection was incomplete with 2/3 of the animal surviving.

In their presentation, Tekmira points to pharmacokinetic
data, especially the maximal drug concentration in serum that was higher in
humans than the monkeys at the same mg/kg dose levels. In other words, Tekmira makes the case that a 0.24mg/kg dose in humans would be therapeutically equivalent to the therapeutic 0.5mg/kg
dose in the monkeys.

It is true that under the Animal Rule, you have to
demonstrate sufficient safety in humans at doses that are pharmacologically
equivalent to those found to be therapeutic in the animal models, and these do
not have to be numerically the same on a mg/kg basis.

However, based on the limited monkey-human PK-PD bridging data provided, I am yet to be fully convinced by this argument. Ideally, there would
be knockdown efficacy data for 3rd gen SNALP available already, data showing that
on a mg/kg basis, 3rd gen knocks down genes slightly more efficiently in humans than in non-human primates.

The best sign that Tekmira is getting crucial buy-in from the FDA
and DoD would be if these agencies were in support of the dose levels chosen by
Tekmira for the multi-ascending dose part of the study that is planned to
start next month (0.06mg/kg, 0.12mg/kg, 0.24mg/kg). The presentation indicated that the
single-ascending dose data is under review by the FDA, and the MAD going ahead
could be a positive sign with regard to agency support.

Long-term research
challenge: new modifications

Long-term, it is still desirable for SNALP to fully wean
itself off from any transient immune suppression at any dose and in any
indication to maximize the therapeutic opportunities. One avenue which I have not seen Tekmira adequately
explore is the use of chemical RNAi trigger modifications beyond 2’-O-methyl. Although Tekmira scientists have nicely shown
that 2-O-methylation can be very effective in dampening the innate
immunostimulatory potential of an RNAi trigger sequence, comparative chemistry studies by ISIS and the
clinical experience by Prosensa indicate that larger modifications on the 2’
position are even more effective in circumventing recognition by innate immune
sensors such as toll-like receptors.

With the healthy cash balance, I would expect Tekmira to reinvigorate
their efforts in identifying even better immune-reducing RNAi trigger chemistries. It could also be a worthwhile endeavor to be
funded under the EBOLA contract as it has been a very successful program so far
in furthering the platform while at the same time developing a biodefense
agent.

14 comments:

Thanks for your comments Dirk. very much appreciated that you took the time to analyze this and present your impressions. Just a couple of points.

1. My impression was the TTR02 was not being administered with steroid/immune suppression. ALNY was using their proprietary microdosing regimen. I think this is a fancy way of saying very slowly.

2. I am not sure that it would be an issue to administer short doses of steroids even in Ebola. Of course the subjects would indeed be in the pre-infective non-symptomatic phase initially. Steroids are immunosuppressive but only in prolonged courses. Acutely the membrane stabilizing effects are used as a hyper-immune response suppressant and there are several instances of severe acute infections e.g. TB, ARDS, H1N1 etc where high dose short course steroids are used to suppress the damage caused by the hyperimmmune response to infection.

3. Bearing in mind that steroids likely would not be a problem it is interesting that TKMR do not feel that steroids or NSAIDS would be needed.

4. Finally since there is an ascending dose of the MAD and there is no consideration of significant single dose toxicity at lower doses it would be very easy to determine whether the MAD did actually achieve the desired dose of the marker targets that were assayed in the SAD. There is no reason why the dose could not be extended beyond 0.24mg/kg if there were no toxicity and the desired blood levels had not been achieved. The P1 is not constrained as P2 or P3 studies might be.

Why hasn't anyone commented on the ground-breaking, unrefrigerated, long shelf-life, 30-times-potent freeze-dried formulation??? That was probably at the request of the US Dept. of Defense. Better for stockpiling and shipping, especially into tropical climate!

30x more potent than what was used in the first-gen EBOLA candidate showing 100% monkey protection at ~2mg/kg.

Not sold a single share though I wished I had waited for the Ebola results to blow over before re-taking my position in Tekmira. Lots of ways to misinterpret the data and yesterday's reaction showed it. On the other hand, at $10.8 TKM-EBOLA and all the other indications for which transient immune suppression is deemed unacceptable have been more than discounted.

Ego...1. ALN-TTR02 employs transient immune suppression;2. I would not exclude that steroids might be beneficial in the overt phase of Ebola infection; however, having them part of the package would complicate interpretation of the results and corresponding studies would have to be performed in monkeys (maybe they have already?);3. It is unclear to me what Tekmira means with 'blanket use' and how to tell patients that should be pre-treated from those that would not need it;4. At this point, I feel it is critical to get buy-in from the agencies before starting the MAD. You want to maintain a collaborative spirit in this.

Not really as the 30x difference relates to genes expressed in the liver. For Ebola, the liver is an important target tissue, but not the only one (e.g. phagocytic cells). It is important now to collect as much PK-PD data in monkeys and humans to get an idea as to how the 0.5mg/kg dose that gave full protection in monkeys relates to human dosages.

What do you make of the statement on s. 33. Where the company summarizes that the "Drug exposureanalysis indicates that a dose of0.24 mg/kg/day will meet exposuretargets derived from the highestdose level currently usedin monkey efficacy studies(0.5mg/kg/day)", i.e. the max dose with the 100% survival rate. Thus they seem to imply that the 0.24 mg/kg dose would produce 100% surv. in humans and thus NOT "only" ~ 67% surv. as the closer 0.20 mg/kg dose did for the monkeys. does this make PK/PD sense to you given the differences between humans and NHPs? Or does this rationale seem inplausible?

Intuitively one might think that they would have got to be quite certain that 0.24 mg/kg is enough for ~ 100% protection... Otherwise, why would they not trie to use the MTD of 0.40 mg/kg or even experiment with doses >0.30mg/kg but <0.5mg/kg in the MAD part of the study.

Furthermore, considering the extremely aggressive nature of EBV and the +9/10 fatality rate, on would expect that the cure might be quite toxic as well.. so could not the doctors theoretically just increase the dose in the real setting if they would deem it necessary for the survival of the patient? I mean, simplistically, does the cure for EBV have to be as safe as an parenteral nutrition, an imaging agent or Well tolerated parenteral Tx (as was the case with the 0.3 mg/kg dose)? Surely a higher AE profile should be acceptable, if needed, considering the fatality rate of EBV?

Dirk - In my opinion, the price action yesterday post the Ebola PR had little to do with the actual PR. TKMR has been dramatically underperforming the other RNAi's for the last month. To me it seems like there's been motivated seller who isn't done..

Why wouldn't Alynlam just do a hostile takeover if their LNP assets are worth as much as you are implying? There may be some bad blood, but what's to stop them acquiring at such a tiny EV and firing everyone?

It is important to notice that EBV also must be delivered outside the liver! Therefore one could hypothetize that a considerably lower dose will be efective in pure play liver targets as HBV. Think about it: ARWR could deliver 2 to 3 mg/kg without DLT's in HBV chimp. Based on the ALNY hbv data reported higher knock down than ARWR at doses ~ 0,20 - 0.5 mg/kg utilizing 2 gen LNP delivery, one may hypothetize that the ~30x more potent (in the liver) 3rd gen LNP, will not have to deliver the Tx at levels even remotely close to 0,5 mg/kg(notwithstanding that 0,5 mg/kg may be perfectly safe in the less frequent HBV dosing regime).

Therefore, i think its quite premature to conclude that the the LNP platform would be unsafe as the 0,30 mg/kg administered safely might translate closer to 9 mg/kg, or even more,(!!) with the ARWR platform, when considering the difference in potency in favor of TKMR's LNP platform. This is, of course, an over simplification, but you simply cannot compare the volumes administered safely with ARWR's platform with TKMR's platform on a simple mk/kg basis without any regard for potency! IMO

(cont.)Or for an other comparison: The TKM-ApoB Tx had DLTs at 0,6 mg/kg (on a slower dosing regime, whereas TKM-EBOV had DLTs on at 0,5 mg/kg (in prob. the most stringent and frequent dosing to date in RNAi Tx human trials, considering that this new LNP formulation is ~30x more potent this does not reflect to badly on the LNP platform.

That said, we'll know more after the start of the MAD and the presentation of pre-clinical TKM-HBV data.

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